Diabetes mellitus is rapidly becoming one of the predominant health concerns of the western world. Fundamentally, diabetes is a failure of the insulin signaling system which functions to maintain blood glucose concentrations within a narrow range. A key component of this system is the pancreatic beta-cell which singularly has responsibility for insulin production and secretion. For proper function, the pancreatic beta-cell is required to make and release large amounts of insulin in response to elevated blood glucose. The subject of this proposal is a system of the beta-cell that increases insulin production in response to elevated blood glucose. We have recently discovered that PASK is an important part of this system at least in isolated beta-cells in the laboratory. The goals of the current proposal are threefold. First, we will study how PASK activity is regulated by glucose concentration. Second, we will determine how PASK stimulates insulin production. Specifically, what other proteins are involved and how does PASK control their function. Third, we will use mice in which PASK has been eliminated to assess the importance of this protein in the natural function of beta-cells. We will examine these mice for defects in the development, maintenance and insulin production of beta-cells. In a larger context, we will examine the mice for global defects that are characteristic of inadequate beta-cell function, such as overt diabetes. We hope to further the understanding of this important beta-cell system for responding to increased blood glucose, and specifically the role of PASK in its operation. [unreadable] [unreadable]